Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-01-16
1998-12-15
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540456, C07D49818, A61K 31445
Patent
active
058497307
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to the field of immunosuppressant macrolides and to processes for preparing demethyl derivatives of rapamycin from rapamycin. The process comprises fermenting the microorganism Actinoplanes sp. ATCC 53771 in the presence of rapamycin.
Rapamycin is an antifungal and immunosuppressant compound having the structure of formula (I), ##STR2## which can be prepared by fermenting Streptomyces hygroscopicus. Rapamycin has been reported to be effective in models for allergic encephalomyelitis, multiple sclerosis, adjuvant rheumatoid arthritis and inhibition of the formation of IgE-like antibodies. Rapamycin has been shown to prolong the survival time of organ grafts in histoincompatible rodents. R. Morris, Med. Sci. Res., 1989, 17, 877. Rapamycin has been shown to inhibit T-cell activation. Strauch, FASEB, 3, 3411, 1989.
Rapamycin has been shown to be useful in combination with Cyclosporin A. This combination has the advantage of reducing the amount of Cyclosporin A required to produce an immunosuppressant effect when given to heart, kidney, bowel, pancreas or other transplant patients. This effectively reduces the nephrotoxicity inherent in Cyclosporin A treatment. Stepkowski, S. M. et al., Transplantation Proceedings, 23,507-08, 1991.
Derivatives of rapamycin have also been reported to have antifungal activity. Additionally, various rapamycin derivatives have been reported to be useful in the treatment of transplantation rejection, host vs. graft disease, autoimmune diseases, diseases of inflammation, solid tumors, and fungal infections. Failli, EP 0 467 606 and Oneydaka, U.S. Pat. No. 5,091,389. C-16 and C-39 demethylrapamycin have themselves been reported to have this activity.
Actinoplanes sp. ATCC 53771, when fermented in the presence of FK520 and FK506, which are also macrolides, has been shown to produce various demethylated analogs of FK520 and FK506. Chen et al., Journal of Antibiotics, 1992, 45, 118-123.
This invention relates to an improved process for the preparation of C-16 and C-39 demethylrapamycin as well as the preparation of C-24 hydroxyrapamycin. This process involves fermenting Actinoplanes sp. ATCC 53771 in the presence of rapamycin to produce C-16 and C-39 demethylrapamycin as well as C-24 hydroxyrapamycin.
SUMMARY OF THE INVENTION
This invention relates to a process for preparing compounds of the formulae ##STR3##
This invention also relates to the compound of the formula (IV) above, which has antifungal activity. Hence this compound can be used to treat or prevent infections in mammals caused by fungi. Accordingly, this invention embraces a method of treating diseases caused by a fungus in a mammal in need of such treatment comprising administering to said mammal an effective amount of the compound of formula (IV) or a pharmaceutically acceptable salt thereof.
Additionally, this invention embraces a pharmaceutical composition comprising the compound of formula (IV) and a pharmaceutically acceptable carrier.
DETAILED DESCRIPTION OF THE INVENTION
The process of this invention is readily carried out. Thus, Actinoplanes sp. ATCC 53771 is fermented in the presence of rapamycin to microbially modify rapamycin, producing C-16-demethylrapamycin, C-39-demethylrapamycin and C-24-hydroxyrapamycin.
A lyophilized sample of Actinoplanes sp. ATCC 53771 was deposited with the American Type Culture Collection, 12301 Parklawn Drive, Rockville, Md., 20852, U.S.A., under the terms of the Budapest Treaty on 8 Jun. 1994. This newly deposited culture was given the new deposit number of ATCC 55586. All restrictions on the availability to the public of the microorganism culture so deposited will be irrevocably removed upon the issuance of a patent from this specification.
Cultures of Actinoplanes sp. ATCC 55586 can be obtained from the American Type Culture Collection. A culture so obtained is added to a suitable growth medium and is incubated with shaking until growth occurs. The cultures thus prepared are used to inoculate slants. Portions of these s
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Vezina, J. Antibiotics, 1975, 28, 721-726.
Chen, J. Antibiotics, 1992, 45, 118-123.
Morris, Med. Sci. Res., 1989, 17, 877.
Strauch, FASEB, 1989, 3, 3411.
Stepkowski, Transplantation Proceedings, 1991, 23, 507-508.
Guadliana Mark A.
Truesdell Susan J.
Benson Gregg C.
Kifle Bruck
Pfizer Inc.
Richardson Peter C.
Ronau Robert T.
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